Jan. 09, 2015

Diet Pill Mimics the Effects of Eating

IRA FLATOW: This is Science Friday, I'm Ira Flatow. If you're finishing up your lunch or you're munching on a snack, don't let me disturb you, but I thought you might like to know what's going on inside your body at this very moment. As you chew on that next bite, your body's flipping a series of chemical switches, setting in motion your gastric juices, the flow of bile, your heart which pumps more blood to your intestines.

The switches also reduce your blood sugar. They send a message to your fat deposits telling them, get ready to pack. We've got an incoming load of calories. But now researchers have figured out how to flip those switches without eating anything, but with a pill. No calories needed.

And that imaginary meal is a pill appears to work. Helps obese mice lose weight, at least. Can it do the same thing for us? Ron Evans is the author of a new study on that discovery in the journal Nature Medicine. He's also an investigator at the Howard Hughes Medical Institute, professor and director of the gene expression lab at the Salk Institute in La Jolla. Welcome back to Science Friday, Dr. Evans.

RON EVANS: Ira, thank you for that wonderful introduction and for the invitation to be here.

IRA FLATOW: Oh, well, you're quite welcome. Tell us how this pill is able to mimic the effects of a full meal without the food.

RON EVANS: Well, it's a great question. The reality is that as soon as you begin eating a meal, your body begins to respond because eating is the key feature of survival. And you can't wait till you finish the meal to begin processing that food. It begins right away.

And what we realized is that process begins in the intestine with the release of a substance called bile acids. Bile acids are a natural product that's produced in the liver, stored in the gallbladder. And when you take that first bite, bile acids begin to be released into the intestine to help solubilize those nutrients in the food so you can absorb them into your body and transport them to tissues where those calories will be stored for later use. So that's the beginning of the food process, and that trigger is bile acids.

IRA FLATOW: So you have found a way of fooling the body into thinking that there is bile acids present when there isn't, then?

RON EVANS: So that was the secret to our study was to try to develop a pill, in this case, that would mimic the bile acid that's produced, but in the form of a pill. It's not bile acid. And that was based on a discovery that we had made actually back in 1995, quite some time ago, that there was a receptor, a type of molecule, in the intestine that is a sensor for bile acids.

And so we built a drug that could interact with that sensor that makes the sensor think, oh, you've just eaten a meal. Bile acid's being produced. But that actual trigger was just our pill.

IRA FLATOW: So the pill is just latching on to the spot where the bile acid would telling your body hey, you should be full. You should be feeling full.

RON EVANS: Exactly. So the more bile acid you produce, typically it's a bigger meal. So the more that we stimulate this switch, this sensor, the more that the body thinks you've had a meal that's coming in and it's beginning to trigger the alert system, food's coming in. Everyone, you know what to do. Stand by.

IRA FLATOW: And you tried this in mice, and did they actually lose weight?

RON EVANS: We tried it in a number of different types of mouse models for obesity and diabetes. And in every model that we examined, interestingly, they lower their glucose, they improve their insulin, and they also increase a process called thermogenesis which causes the mice to lose weight.

IRA FLATOW: Wow. Another interesting thing you found is that this pill causes white fat to go brown. Why is that a good thing?

RON EVANS: We have two types of fat in our body. One's white fat, which is what stores most of the fat for those times of famine. So that's like your belly fat. And most of your calories you eat in a meal will go to that particular depot and be stored there. The safe opens up, the calories go in, and then the safe closes and they're locked in there.

There's another type of fat called brown fat that is not designed so much for storage. It is actually designed to burn fat. So that tissue burns fat and converts it into heat, a process called thermogenesis.

And when you do that, you release that heat into your body. And many animals in the wild like squirrels in Central Park, for example, when it gets cold they will use a process called shivering thermogenesis. They'll start to shake a little bit, and they'll burn through this brown adipose tissue, the fat that's stored there, and create heat.

And animals that are in the cold in the winter can actually survive really cold days by creating internal forms of heat. Humans, we're also born with brown fat and white fat, but we mostly favored using the white fat because we tend to put on a lot of clothes and live in environments where we don't need to use brown fat. And so our brown fat switch is pretty much off all the time unless you are running around, jumping into freezing water, and that sort of thing.

But typically, it's difficult to trigger the process to turn on. What we found in the mice is that this pill that we give to the mice triggers this response only in the intestine, but it has an unexpected consequence of triggering this thermogenic response in the rest of the body, and therefore the mice actually lose weight.

IRA FLATOW: So is this ready for prime time yet?

RON EVANS: Ready for prime time. Well, conceptually we went through a major milestone in showing that a drug-- and I should mention this drug does not actually get into the body. It does not need to be brought into the bloodstream to do its work. It stays in the intestine and it just passes through the body, so it has a major safety feature, number one.

But number two, it acts, because of that, as the first responder in a cascade of events that are involved in digestion. And that's the way normal food works. So we think that the proof of principle is in place, especially using these obese diabetic mice to show how to do this. Since we have started this particular project, we've made several new generations of derivatives of this drug that would be more appropriate for human use.

IRA FLATOW: We talked to you a few years back about something dubbed the exercise pill. Exercise in a pill that increased endurance in mice.

RON EVANS: Yes.

IRA FLATOW: Is that related to this work?

RON EVANS: Well, it's another type of thing where that pill is like imaginary exercise. That's a pill that targets muscle. So this is a pill the targets another process that involves how we manage energy. So muscle is the tissue the burns energy, but the intestine is the tissue that brings energy into the body.

There is a whole order of things. So in one case, we're looking at the end tissue, which is muscle. And we're able to activate that to think it is being exercised. And two things happen. It burns energy, it burns sugar and fat so that those levels go down in your body. So you actually do lose weight as well. And you improve your ability to actually perform.

So mice that get that pill were able to run longer. The history of that story, which is still going on, is that that particular drug became popular in athletes and it's now a banned substance. And it is still being used by quite a few athletes worldwide, and they're being tested for it. But that's a drug that was really built for our studies, and we've now re-crafted that to be a better safer drug for people and we're moving it forward into clinical trials.

IRA FLATOW: Let's talk about this new pill that you have that mimics eating.

RON EVANS: Yeah.

IRA FLATOW: Since this fools you into thinking that the bile is flowing, so to speak, could the pill treat bile disorder by taking the place and locking into the places that the bile would be, but you don't have any. Or maybe you've lost your ability to make it.

RON EVANS: That is a great question. There are a lot of diseases, actually, that are linked to poor bile acid properties. And several diseases of the liver that involve either destruction of the liver itself. They're linked to problems with bile acid management. And also diseases in the intestine called biliary diarrhea or bile acid diarrhea that are major problems for people.

And we believe that this could have a major benefit in several areas where the disease is currently not treated. So intestinal diseases in specific we think could be-- I don't want to call low hanging fruit. But many of them are difficult to manage such as intestinal inflammatory disease, or bowel disease, IBD, and Crohn's disease are major problems for people, and they're not well managed problems.

And so that's an area where we believe there could be some benefit also in the bile acid problems in the liver where the patients have tremendous problems often leading to liver transplant where this pathway could be very effective.

IRA FLATOW: So we've got a ways to go. You obviously have not started human trials on this.

RON EVANS: We have not started human trials yet, yeah.

IRA FLATOW: Yeah. Well, we'll be in touch, Dr. Evans. Thank you for taking time to be with us today.

RON EVANS: Great pleasure to be here, and thank you for the invitation.

IRA FLATOW: You're welcome. Ron Evans is an investigator at the Howard Hughes Medical Institute, professor and director of the gene expression lab at the Salk Institute in La Jolla, California.

CLOSE

When we eat, a series of chemical switches turns on, releasing bile, lowering blood sugar, and ramping up blood flow to the intestines. Fat stores are activated too, burning old calories to prep for the new ones in your meal. But now researchers have figured out how to hijack that process with a pill—no calories needed. Ronald Evans describes the finding this week in the journal Nature Medicine. So far, he and his colleagues have shown that the “imaginary meal” pill works in mice, helping them to shed extra weight. Can it do the same in humans?

IRA FLATOW: This is Science Friday, I'm Ira Flatow. If you're finishing up your lunch or you're munching on a snack, don't let me disturb you, but I thought you might like to know what's going on inside your body at this very moment. As you chew on that next bite, your body's flipping a series of chemical switches, setting in motion your gastric juices, the flow of bile, your heart which pumps more blood to your intestines.

The switches also reduce your blood sugar. They send a message to your fat deposits telling them, get ready to pack. We've got an incoming load of calories. But now researchers have figured out how to flip those switches without eating anything, but with a pill. No calories needed.

And that imaginary meal is a pill appears to work. Helps obese mice lose weight, at least. Can it do the same thing for us? Ron Evans is the author of a new study on that discovery in the journal Nature Medicine. He's also an investigator at the Howard Hughes Medical Institute, professor and director of the gene expression lab at the Salk Institute in La Jolla. Welcome back to Science Friday, Dr. Evans.

RON EVANS: Ira, thank you for that wonderful introduction and for the invitation to be here.

IRA FLATOW: Oh, well, you're quite welcome. Tell us how this pill is able to mimic the effects of a full meal without the food.

RON EVANS: Well, it's a great question. The reality is that as soon as you begin eating a meal, your body begins to respond because eating is the key feature of survival. And you can't wait till you finish the meal to begin processing that food. It begins right away.

And what we realized is that process begins in the intestine with the release of a substance called bile acids. Bile acids are a natural product that's produced in the liver, stored in the gallbladder. And when you take that first bite, bile acids begin to be released into the intestine to help solubilize those nutrients in the food so you can absorb them into your body and transport them to tissues where those calories will be stored for later use. So that's the beginning of the food process, and that trigger is bile acids.

IRA FLATOW: So you have found a way of fooling the body into thinking that there is bile acids present when there isn't, then?

RON EVANS: So that was the secret to our study was to try to develop a pill, in this case, that would mimic the bile acid that's produced, but in the form of a pill. It's not bile acid. And that was based on a discovery that we had made actually back in 1995, quite some time ago, that there was a receptor, a type of molecule, in the intestine that is a sensor for bile acids.

And so we built a drug that could interact with that sensor that makes the sensor think, oh, you've just eaten a meal. Bile acid's being produced. But that actual trigger was just our pill.

IRA FLATOW: So the pill is just latching on to the spot where the bile acid would telling your body hey, you should be full. You should be feeling full.

RON EVANS: Exactly. So the more bile acid you produce, typically it's a bigger meal. So the more that we stimulate this switch, this sensor, the more that the body thinks you've had a meal that's coming in and it's beginning to trigger the alert system, food's coming in. Everyone, you know what to do. Stand by.

IRA FLATOW: And you tried this in mice, and did they actually lose weight?

RON EVANS: We tried it in a number of different types of mouse models for obesity and diabetes. And in every model that we examined, interestingly, they lower their glucose, they improve their insulin, and they also increase a process called thermogenesis which causes the mice to lose weight.

IRA FLATOW: Wow. Another interesting thing you found is that this pill causes white fat to go brown. Why is that a good thing?

RON EVANS: We have two types of fat in our body. One's white fat, which is what stores most of the fat for those times of famine. So that's like your belly fat. And most of your calories you eat in a meal will go to that particular depot and be stored there. The safe opens up, the calories go in, and then the safe closes and they're locked in there.

There's another type of fat called brown fat that is not designed so much for storage. It is actually designed to burn fat. So that tissue burns fat and converts it into heat, a process called thermogenesis.

And when you do that, you release that heat into your body. And many animals in the wild like squirrels in Central Park, for example, when it gets cold they will use a process called shivering thermogenesis. They'll start to shake a little bit, and they'll burn through this brown adipose tissue, the fat that's stored there, and create heat.

And animals that are in the cold in the winter can actually survive really cold days by creating internal forms of heat. Humans, we're also born with brown fat and white fat, but we mostly favored using the white fat because we tend to put on a lot of clothes and live in environments where we don't need to use brown fat. And so our brown fat switch is pretty much off all the time unless you are running around, jumping into freezing water, and that sort of thing.

But typically, it's difficult to trigger the process to turn on. What we found in the mice is that this pill that we give to the mice triggers this response only in the intestine, but it has an unexpected consequence of triggering this thermogenic response in the rest of the body, and therefore the mice actually lose weight.

IRA FLATOW: So is this ready for prime time yet?

RON EVANS: Ready for prime time. Well, conceptually we went through a major milestone in showing that a drug-- and I should mention this drug does not actually get into the body. It does not need to be brought into the bloodstream to do its work. It stays in the intestine and it just passes through the body, so it has a major safety feature, number one.

But number two, it acts, because of that, as the first responder in a cascade of events that are involved in digestion. And that's the way normal food works. So we think that the proof of principle is in place, especially using these obese diabetic mice to show how to do this. Since we have started this particular project, we've made several new generations of derivatives of this drug that would be more appropriate for human use.

IRA FLATOW: We talked to you a few years back about something dubbed the exercise pill. Exercise in a pill that increased endurance in mice.

RON EVANS: Yes.

IRA FLATOW: Is that related to this work?

RON EVANS: Well, it's another type of thing where that pill is like imaginary exercise. That's a pill that targets muscle. So this is a pill the targets another process that involves how we manage energy. So muscle is the tissue the burns energy, but the intestine is the tissue that brings energy into the body.

There is a whole order of things. So in one case, we're looking at the end tissue, which is muscle. And we're able to activate that to think it is being exercised. And two things happen. It burns energy, it burns sugar and fat so that those levels go down in your body. So you actually do lose weight as well. And you improve your ability to actually perform.

So mice that get that pill were able to run longer. The history of that story, which is still going on, is that that particular drug became popular in athletes and it's now a banned substance. And it is still being used by quite a few athletes worldwide, and they're being tested for it. But that's a drug that was really built for our studies, and we've now re-crafted that to be a better safer drug for people and we're moving it forward into clinical trials.

IRA FLATOW: Let's talk about this new pill that you have that mimics eating.

RON EVANS: Yeah.

IRA FLATOW: Since this fools you into thinking that the bile is flowing, so to speak, could the pill treat bile disorder by taking the place and locking into the places that the bile would be, but you don't have any. Or maybe you've lost your ability to make it.

RON EVANS: That is a great question. There are a lot of diseases, actually, that are linked to poor bile acid properties. And several diseases of the liver that involve either destruction of the liver itself. They're linked to problems with bile acid management. And also diseases in the intestine called biliary diarrhea or bile acid diarrhea that are major problems for people.

And we believe that this could have a major benefit in several areas where the disease is currently not treated. So intestinal diseases in specific we think could be-- I don't want to call low hanging fruit. But many of them are difficult to manage such as intestinal inflammatory disease, or bowel disease, IBD, and Crohn's disease are major problems for people, and they're not well managed problems.

And so that's an area where we believe there could be some benefit also in the bile acid problems in the liver where the patients have tremendous problems often leading to liver transplant where this pathway could be very effective.

IRA FLATOW: So we've got a ways to go. You obviously have not started human trials on this.

RON EVANS: We have not started human trials yet, yeah.

IRA FLATOW: Yeah. Well, we'll be in touch, Dr. Evans. Thank you for taking time to be with us today.

RON EVANS: Great pleasure to be here, and thank you for the invitation.

IRA FLATOW: You're welcome. Ron Evans is an investigator at the Howard Hughes Medical Institute, professor and director of the gene expression lab at the Salk Institute in La Jolla, California.